Despierre Evelyn, Yesilyurt Betül T, Lambrechts Sandrina, Johnson Nick, Verheijen René, van der Burg Maria, Casado Antonio, Rustin Gordon, Berns Els, Leunen Karin, Amant Frédéric, Moerman Philippe, Lambrechts Diether, Vergote Ignace
*Gynecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven; and †Laboratory for Translational Genetics, Department of Oncology, Katholieke Universiteit Leuven; and ‡Vesalius Research Center, VIB, Leuven, Belgium; §Royal United Hospital NHS Trust, Gynaecological Oncology, Bath, United Kingdom; ∥Division of Women and Baby, Department of Gynaecological Oncology, University Medical Centre Utrecht; and ¶Department of Medical Oncology, Erasmus University Medical Center-Cancer Institute, Rotterdam, the Netherlands; #Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain; **Medical Oncology, Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex, United Kingdom; and ††Department of Pathology, University Hospitals Leuven, Belgium.
Int J Gynecol Cancer. 2014 Mar;24(3):468-77. doi: 10.1097/IGC.0000000000000089.
Epithelial ovarian cancers (EOCs) are, although still treated as a single disease entity, often classified into type I tumors (low-grade serous, mucinous, endometrioid, clear cell) and type II tumors (high-grade serous, undifferentiated cancers, carcinosarcomas). The aim of our study was to determine the incidence, clinical relevance, and prognostic and predictive impact of somatic mutations in both types I and II EOCs.
Two hundred sixty-two evaluable, primary, high-risk stage I (grade 3, or aneuploid grade 1 or 2, or clear cell) and stage II-IV EOCs, collected at the University Hospitals Leuven and within the European Organisation for Research and Treatment of Cancer 55971 trial, were genotyped for hotspot mutations in KRAS (COSMIC [Catalogue of Somatic Mutations in Cancer] coverage >97%), BRAF (>94%), NRAS (>97%), PIK3CA (>79%), PTEN, FBXW7 (>57%), AKT2, AKT3, and FOXL2, using Sequenom MassARRAY.
Of the 13% histopathologically classified type I tumors, 49% were KRAS or PIK3CA mutant versus only 2.9% in the type II tumors (87%). Mucinous subtypes harbored significantly more KRAS mutations than all nonmucinous tumors (50% vs 4%, P < 0.001). PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis. Moreover, low-grade serous tumors were more frequently KRAS or BRAF mutated (44%) than high-grade serous tumors (0.6%). KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival. Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%).
Somatic mutations are rare in type II EOCs, whereas type I EOCs contain distinct diseases with different driver mutations. In general, these tumors respond worse to standard paclitaxel carboplatin therapy. Clinical trials with molecular targeted therapy in the different subtypes of type I tumors are urgently needed using this theragnostic information.
上皮性卵巢癌（EOC）虽仍被视为单一疾病实体，但常分为I型肿瘤（低级别浆液性、黏液性、子宫内膜样、透明细胞癌）和II型肿瘤（高级别浆液性、未分化癌、癌肉瘤）。我们研究的目的是确定I型和II型EOC中体细胞突变的发生率、临床相关性以及预后和预测影响。
在鲁汶大学医院收集的262例可评估的原发性高危I期（3级，或非整倍体1级或2级，或透明细胞癌）和II-IV期EOC，以及欧洲癌症研究与治疗组织55971试验中的样本，采用Sequenom MassARRAY对KRAS（癌症体细胞突变目录[COSMIC]覆盖度>97%）、BRAF（>94%）、NRAS（>97%）、PIK3CA（>79%）、PTEN、FBXW7（>57%）、AKT2、AKT3和FOXL2的热点突变进行基因分型。
在组织病理学分类为I型的肿瘤中，13%为KRAS或PIK3CA突变型，而II型肿瘤中这一比例仅为2.9%（87%）。黏液性亚型的KRAS突变明显多于所有非黏液性肿瘤（50%对4%，P<0.001）。PIK3CA突变主要见于透明细胞癌（46.2%）和子宫内膜样癌（20%），且常与子宫内膜异位症相关。此外，低级别浆液性肿瘤的KRAS或BRAF突变频率（44%）高于高级别浆液性肿瘤（0.6%）。KRAS或PIK3CA突变与无进展生存期或总生存期无关。NRAS、PTEN、FBXW7、AKT2、AKT3和FOXL2的突变罕见（<1%）。
体细胞突变在II型EOC中罕见，而I型EOC包含具有不同驱动突变的不同疾病。总体而言，这些肿瘤对标准紫杉醇-卡铂治疗反应较差。迫切需要利用这些治疗诊断信息，针对I型肿瘤的不同亚型开展分子靶向治疗的临床试验。
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